The present invention relates generally to sterile, polymerizable compositions together with systems, kits, and methods for the sterile manufacture, packaging, and delivery of same. More particularly, the present invention relates to sterile, polymerizable systems and kits that are comprised of pre-mixed, viscous, sterile compositions, especially restorative, and methods of making same.
Sterilization is generally defined as rendering a substance incapable of reproduction. In terms of food, medical products or pharmaceuticals, sterilization relates to rending an article free from living microorganisms. The rate of destruction of microorganisms is logarithmic and can be described by the following expression:
No/Nt=exe2x88x92kt
wherein Nt represents the number of organisms alive at time xe2x80x98txe2x80x99, No represents the initial number of organisms, and k equals the kinetic rate constant.
A common manner of expressing sterilization is the sterility assurance level (xe2x80x9cSALxe2x80x9d). Because microbiological destruction is logarithmic and expressed in terms of the probability of a survivor, the term xe2x80x9csterile devicexe2x80x9d does not actually refer to a device that is totally free of viable organisms, but rather to one whose probability of containing a viable organism is so small that it is considered acceptable for a given purpose. Hence, the sterility assurance level (SAL) defines the probability of a viable microorganism being present on an article after sterilization is complete. According to the present FDA regulations, topical medical devices should have a minimum SAL of 10xe2x88x923 whereas devices or articles that will directly contact blood or compromised tissues should have a minimum SAL of 10xe2x88x926. The integrity of the sterilization method is generally monitored by culturing a test organism. For example, the remaining presence of the highly heat-resistant bacterium, bacillus subtilis globigii, can be used as a marker to measure the completeness of sterilization.
There are many different methods of sterilization, each of which presents numerous advantages and disadvantages depending upon the nature of the article or medium to be sterilized. Some of these methods involve the application of heat, pressure, and/or moisture. Moist heat sterilization, i.e., boiling, kills all vegetative cells, most viruses, and fungi within 10 minutes. However, moist heat sterilization is not suitable for many applications in biology and medicine because it causes coagulation of proteins and breakage of hydrogen bonds contained therein.
Another method of sterilization, known as steam sterilization, is the application of steam under pressure within an enclosed chamber known as an autoclave. This method subjects the media to temperatures of typically 121xc2x0 C. at pressures of 15 pounds per square inch (xe2x80x9cpsixe2x80x9d) above ambient. Autoclave sterilization is capable of killing all microorganisms and their endospores in about 15 minutes. The efficacy of autoclave sterilization is measured by determining the presence or absence of bacillus stearothermophilus spores. Media or substances stable in heat may be sterilized at higher temperatures for shorter time periods; conversely, sterilization at lower temperatures require longer sterilization periods.
Dry heat sterilization may involve incineration, i.e., exposing media to high temperatures such as 180xc2x0 C., or hot-air sterilization, i.e., exposing media to controlled time and temperature conditions. This method is suitable for media such as pharmaceutical products that do not contain water as their primary solvent and cannot be sterilized by other methods. In this instance, dry heat is applied to the media at temperatures of about 100xc2x0 C. to about 250xc2x0 C. and exposure times ranging from about one to four hours. The temperature-time relationship is similar to that of steam sterilization.
Sterilization can also occur through the filtration or the physical retardation of microorganisms from a fluid medium by a filter membrane.
Still other methods of sterilization involve the application of radiation, either ionizing or non-ionizing, to sterilize the media. Ionizing radiation involves the application of shorter wavelength radiation, such as gamma rays, beta-rays, x-rays, or high energy electron beams, to ionize the water particles contained within the media to form reactive hydroxyl radicals. This method is commonly used to sterilize pharmaceutical products or disposable dental and medical supplies such as syringes, gloves, or sutures. Activated resins such as those used in bone cements, however, cannot be gamma sterilized because it effects the polymerization process. Non-ionizing radiation involves the application of ultraviolet rays to cause the formation of thymine dimers that inhibit the replication of DNA. Although these rays are non-penetrating to the media, some media can be destroyed in the doses required for effective sterilization.
Another sterilization method is gas sterilization, in which the media is exposed to a vapor or gas such as ethylene oxide (xe2x80x9cEtOxe2x80x9d). This method is suitable for media, such as foods, pharmaceuticals, and medical equipment, that cannot withstand the temperatures and moisture of steam sterilization or cannot be exposed to radiation. A gaseous sterilant, such as ethylene oxide, is applied under controlled temperature, time, gas concentration, and relative humidity parameters that vary depending upon the nature of the media to be sterilized. Important considerations in the selection of a gas sterilant is the ability of the residue remaining on the media after exposure to the sterilant to volatilize quickly. Because gas sterilization may involve the use of chlorofluorocarbons (xe2x80x9cCFCxe2x80x9d), plasma gas sterilization, which is a low temperature gas sterilization process involving hydrogen peroxide or other sterilants in the plasma state, is an alternative that is generally safe for the environment. However, plasma technology is currently even more limited than EtO sterilization in terms of what media it can sterilize.
Once an article is sterilized, it needs to be packaged in a manner that will not compromise its sterility until use. Sterilization packaging typically takes place at one location prior to use of the medium, or article, at another location. The main purpose of this packaging is to protect the sterility of the internal contents. Terminal sterilization describes the process of placing an article within its protective container and subsequently sterilizing the container and the article contained therein. On the other hand, aseptic processing involves placing individually sterilized components that have been sterilized by various sterilized methods into a sterilized package that is sealed under sterile conditions. The packaging containers used in these processes are sterilized separately and remain in a sterile environment prior to use. The packaging machinery that is used to fill the packaging containers is also sterilized using steam, sterile gases, or hydrogen peroxide.
Pharmaceutical products are typically rendered sterile by aseptic processing. In aseptic processing, the separate ingredients of a medium, such as a pharmaceutical, are available in sterile form and compounded without microbial contamination. Pharmaceuticals that are injectable may be comprised of aqueous or oily solutions, suspensions or emulsions, and are prepared by conventional manufacturing methods, with special care taken to remove all extraneous particulate matter. Injections must be sterilized by any of the methods given above or terminally sterilized. Some aqueous injectables are not stable and need to be prepared at the time of use by mixing some components prior to use. In this instance, the end user is provided a kit and must assemble the ingredients in a sterile environment immediately prior to injection.
An example of a multi-component system, that must be assembled by the end-user in a sterile environment prior to use, are biocompatible, restorative compositions or biomaterials that are used in orthopaedic and dental applications. Typically, these biomaterials are comprised of a solid component and a liquid component. The solid component may consist of a finely divided polymer of acrylic and/or methacrylic esters and further additives such as polymerization initiators, radiographic contrast agents, and fillers. A typical example of such a powder may consist of small spherical beads (usually about 75 xcexcm in diameter) of poly (methyl methacrylate) (PMMA) and a small amount of a polymerization initiator such as benzoyl peroxide. The liquid component may consist of an acrylic and/or methacrylic ester monomer and further additives such as polymerization accelerators and stabilizers. A typical example of a liquid is a methyl methacrylate (MMA) monomer, a polymerization activator such as N,N-dimethyl-para-toludine, and an inhibitor such as hydroquinone. The solid and liquid components are combined immediately prior to use to form a liquid to semisolid paste. The paste may be formed into a desired shape or applied via injection in a wide-mouth syringe or spatula to the implantation site of a prosthesis where it polymerizes.
Presently known products feature deactivated resins which are activated upon combination with other components immediately prior to their delivery or use. These resins and other components are individually wrapped and packaged in an overall aseptic package or kit. An example of such a kit is SIMPLEX(copyright) bone cement manufactured by Howmedica of Rutherford, N.J. SIMPLEX(copyright) bone cement is comprised of an aseptically packaged ampule of a liquid methyl methacrylate (xe2x80x9cMMAxe2x80x9d) that is combined with an gamma sterilized bag of powder which comprises pre-polymerized MMA-styrene and barium sulfate (BaSO4). The end user opens the outer packaging, the ampule, and the bag of powder and combines the liquid and powder components. The user then fills a syringe with the cement in order to deliver the cement to the patient. Some of the disadvantages to this product include product variability; lack of assurance that the components are used in compliance with the manufacturer""s instructions; concern over the integrity of the sterilized components; and a shortened time window between preparation of the cement and delivery to the patient. Traditional terminal sterilization is not possible where unpolymerized components must retain activation viability to be delivered to the surgical suite.
There is a need to provide methods for the sterilization and delivery of viscous, multi-component compositions without requiring the end-user to pre-mix or assemble the components. Accordingly, one object of the present invention is to provide a sterile, multi-component, ready to use product that does not require extensive pre-mixing or assembly.
Another object of the present invention is to provide a method for the sterilization of products comprising activated resins or monomers.
Yet another object of the present invention is to provide a method for the sterilization of products comprising heat degradable fillers.
A further object of the present invention is to provide methods for the sterile manufacture and delivery of viscous, multi-component compositions.
An additional object of the present invention is to provide kits comprising the sterile, viscous restorative compositions of the present invention and delivery vessels that allow mixing of these compositions prior to use.
The present invention overcomes the difficulties in the sterilization and delivery of viscous, multi-component compositions that require pre-mixing prior to usage by disclosing a sterile, multi-component, ready-to-use product wherein each component is sterilized independently and then assembled into a sterilized delivery kit. These systems are suitable for, but not limited to, medical or dental applications that utilize bone cement and restorative compositions. The end products delivered from these kits are sterile upon dispensing. The end user does not need a separate sterile area to pre-mix or assemble the restorative compositions prior to use. The present invention further provides methods for the sterilization of the individual components that comprise the paste compositions that will not adversely alter the characteristics of these components. Moreover, the present invention discloses unique delivery vessels that allow for the premixing of one or more paste compositions prior to and upon delivery of the sterile end product.
The present invention provides one or more viscous, sterile paste compositions, referred to herein as pastes, that are pre-blended and sterile upon delivery to form one or more homogeneous blends. Each sterile, viscous paste is comprised of one or more polymerizable monomers or resin components and one or more fillers. The monomers and fillers are initially and individually sterilized, and then blended together to form one or more sterile viscous pastes. The paste is packaged within a sterile delivery vessel that contains one or more cartridges to house the paste. In multiple paste systems, the pastes are dispensed from their respective cartridges and blended together within the delivery vessel to form at least one viscous, homogeneous blend immediately prior to or upon dispensing.
The polymerizable monomer or resin components that comprise the viscous, paste compositions are preferably ethylenically unsaturated monomers, and more preferably, comprise an acrylate. Examples of such monomers in one such composition include, but are not limited to, bisphenol-A-diglycidyl methacrylate (bis GMA), triethyleneglycol dimethacrylate (TEGDMA), diurethane dimethacrylate (DUDMA), and bisphenol-A-ethyl methacrylate (bis-EMA). In preferred embodiments, the monomers within the paste are activated prior to sterilization. Further additions to the paste may include, but are not limited to, polymerization activators, polymerization initiators, radio pacifiers, reinforcing components (i.e., fibers, particles, micro spheres, flakes, etc.), bioactive fillers, neutralizing resins, diluting resins, antibiotic agents, coloring agents, coupling agents, or radiographic contrast agents. Examples of such additives include, but are not limited to, butylhydroxytoluene (BHT), N,N-dimethyl-p-toluidine (DMEPT), tetraethylene glycol dimethyaniline (TEGDMA), dihydroxyethyl-p-toluidine (DHEPT), UV-9, and benzoyl peroxide (BPO).
The monomers and other additives are combined to form a paste composition precursor which is sterilized prior to adding one or more fillers. The preferred method of sterilization of these monomers and other additives that comprise the paste composition precursor is via high pressure filtration. The monomers, which are preferably activated, are passed through a filter such as a 0.22 xcexcm filter to exclude pathogens. The filtration process is conducted under pressures which range between ambient and 200 psi and more preferably between 2-40 psi. The housing and plumbing fixtures used downstream in the filtration process (including the filter itself) are also sterilized prior to use via steam sterilization (i.e., steam sterilization in place (xe2x80x9cSIPxe2x80x9d) or autoclaving), or similar means, to eliminate or minimize contamination.
In addition to the monomer, the viscous paste or pastes further comprise one or more fillers. These fillers may possess a variety of morphologies such as, but not limited to, needles, particulate, flakes, cylinders, long fibers, whiskers, or spherical particles. In preferred embodiments, the filler is comprised of particles with an average particle size ranging from about less than 1.0 xcexcm up to several millimeters (mm). Preferably, the average particle size distribution ranges from 5 to 20 xcexcm.
The filler may be comprised of an inorganic or organic material. In preferred embodiments, the filler is comprised of an inorganic material. Examples of suitable fillers include, but are not limited to, barium glass, barium-boroaluminosilicate glass, silica, 45S5 glass, bioactive glass, ceramics, glass-ceramics, bioactive synthetic combeite glass-ceramic or combinations thereof. The filler or fillers are generally pre-dried prior to blending with other fillers. In preferred embodiments, one or more fillers are coated with silane prior to sterilization.
The filler may be sterilized by dry heat, E beam, bright light, gamma or EtO methods. The filler is preferably sterilized via dry heat sterilization, i.e., exposed to dry heat at a time and temperature sufficient to render it sterile. If the filler is coated with silane, the sterilization method selected should maintain the integrity of the silane coating. In certain embodiments wherein one or more fillers are coated with silane, the filler is dry heat sterilized with minimal heat penetration to yield a minimally degraded silane surface chemistry. The filler is preferably heated to a temperature of about 140xc2x0 C. or less for a period of between about 6 hours to about 12 hours, or more preferably, heated to a temperature of about 121xc2x0 C. for at least 8 hours. In alternative embodiments, the filler can be heated to higher temperatures, such as, but not limited to, temperatures of from about 100xc2x0 C. to about 250xc2x0 C. for inversely proportional time periods or shorter periods of time at higher temperatures.
After the filler and the monomer are sterilized, the filler and monomer are combined to form one or more paste compositions. In preferred embodiments, the monomer and filler are combined to form one or more pastes in an aseptic process, i.e., using equipment that has been pre-sterilized and combining the components of the paste in a class 100 or greater clean room. The equipment used to blend the paste or pastes, such as the mixing equipment, spatulas, blades etc., are preferably pre-sterilized using steam or autoclave sterilization.
The paste is preferably contained within a primary packaging which comprises one or more cartridges, caps, O-ring pistons, and external pouches. Each of these components are sterilized prior to the aseptic filling of the paste or pastes. In preferred embodiments, the primary packaging components are sterilized via gamma sterilization.
One or more pastes are aseptically filled into individual cartridges that further comprise a cap and an O-ring piston. The pastes are fed into their respective cartridge barrels using an aseptic filling process as described herein. Air is removed from the cartridge prior to piston insertion. The piston is then assembled into the cartridge to form an air-tight seal. The filled cartridge and piston are then packaged within at least one external pouch. In preferred embodiments, the filled cartridges and piston assemblies are packaged within a dual pouch arrangement, or an inner and outer pouch. The cartridges are then thermally sealed and labeled. The previous steps, of filling the cartridges, assembling the piston into the cartridge, encapsulating the cartridges into one or more pouches and then thermo-sealing the cartridges, are conducted within an isolated system referred to herein as an isolator. The isolator preferably employs vaporous hydrogen peroxide (VHP) to ensure a sterile environment for the preceding process steps.
Further components, that may comprise the delivery system and kit, include a delivery gun and one or more tips, referred to herein as xe2x80x9cmix tipsxe2x80x9d, that enable mixing and dispensing of the paste or pastes. Additional components to the systems of the present invention may include a micro delivery system. All of these components are sterile or sterilized and packaged prior to use. In preferred embodiments, these components are sterilized via gamma sterilization. After sterilization is completed, the components are placed with an external package to ensure sterility. An example of this external package may include an oxygen permeable membrane such as a TYVEK(copyright)/polyester pouch manufactured by Tolas Healthcare Packaging of Feasterville, Pa. Still other external packages may include, but not be limited to, foil pouches, opaque pouches for light sensitive materials, or other breathable or permeable pouches.
The present invention also discloses methods of preparing a sterile, polymerizable blend. This method comprises the steps of: applying dry heat under time and temperature conditions sufficient to sterilize at least one filler; passing a plurality of polymerizable monomers (or dimers or trimers) through a filter; and combining the monomers and the filler together to form at least one homogeneous blend contained within a first vessel wherein the combined monomers and fillers are dischargeable from a final sterile delivery vessel.
The present invention also discloses sterile, biologically compatible restorative compositions that comprise: a plurality of polymerizable monomers, the monomers having been sterilized by passing them through a filter; at least one filler which has been exposed to conditions of time and temperature effective to render the filler sterile; and the monomers and the filler being blended together to form at least one homogeneous composition contained within a sterile delivery vessel wherein the combined monomers and fillers are dischargeable from the sterile delivery vessel.
Further embodiments disclosed are methods for preparing a sterile, biologically compatible restorative composition. This method comprises the steps of: applying dry heat under time and temperature conditions sufficient to sterilize at least one filler; passing a plurality of polymerizable monomers through a filter, preferably sized to exclude pathogens; and combining the monomers and filler together to form at least one homogeneous composition contained within a sterile delivery vessel. Yet further embodiments of the present invention include sterilization methods for the activated monomer and the silane-coated filler that comprise the paste.
Additional embodiments of the present invention may include shaped bodies made of a sterile polymerizable blend, wherein the blend comprises a plurality of polymerizable monomers, the monomers having been sterilized by passing them through a filter preferably sized to exclude pathogens; at least one filler which has been exposed to conditions of time and temperature effective to render the filler sterile; and the monomers and the filler being blended together to form at least one homogeneous blend contained within a sterile delivery vessel.
Lastly, embodiments of the present invention include methods of restoring tissue in an animal wherein the method comprises the steps of: applying dry heat under time and temperature conditions sufficient to sterilize at least one filler; passing a plurality of polymerizable monomers through a filter sized so as to exclude pathogens; combining the monomers and the filler together to form at least one homogeneous composition contained within a sterile delivery vessel; and applying the composition to an animal whereby the tissue may be restored.